The present invention relates to a new vaccine/immunisation for the prevention and/or prophylaxis against measles virus infection and to a pharmaceutical or therapeutic composition for the treatment of IBD(Inflammatory Bowel Disease); particularly Crohn""s Disease and Ulcerative Colitis and regressive behavioural disease (RBD)(also referred to as xe2x80x9cRegressive Developmental Disorderxe2x80x9d).
In my earlier Patent Application No. WO 96/30544 I have described how persistent measles virus infection whether of a wild type or vaccine mediated is the origin of some forms of IBD.
The latest and most comprehensive population-based epidemiological studies put the prevalence of IBD in the United Kingdom population alone at 1 in 185 at the age of 26 rising to 1 in 140 at the age of 31. Since prevalence of these diseases increases with age to give a peak onset in the 30 to 35 year age group, this level is due to reach 1 in 80 by the age of 45. This rise is particularly conspicuous in children where the instance of Crohn""s Disease has risen by a factor of up to 6 in some areas since 1968.
At present vaccination is used for the prophylactic prevention of measles virus infection and as a public health measure has proved to be generally effective. Infants are injected with an attenuated virus often within the second year of life and lately a booster vaccination schedule has been introduced to all school children approaching primary school age.
Unfortunately as I have shown previously in the above mentioned patent application the use of this vaccine has been shown to be instrumental in development of Crohn""s Disease and other forms of IBD over the ensuing 30 to 40 years and particularly has been instrumental in a substantial increase in Crohn""s Disease in children since vaccination was started in 1968.
It has now also been shown that use of the MMR vaccine (which is taken to include live attenuated measles vaccine virus, measles virus, mumps vaccine virus and rubella vaccine virus, and wild strains of the aforementioned viruses) results in ileal lymphoid nodular hyperplasia, chronic colitis and regressive developmental disorder including autism (RBD), in some infants. Before vaccination infants were shown to have a normal developmental pattern but often within days to weeks of receiving the vaccination some infants can begin to noticeably regress over time leading to a clinical diagnosis of autism. The MMR vaccine was first used in 1968 and a study in Sweden has shown recently that the prevalence of children with autism has significantly risen. The study has shown that the autistic spectrum of disorders may now affect 1% of the population.
The Physician is therefore confronted with a difficulty at the individual level in that whereas as a public health measure measles vaccination is called for, it can have unwanted effects in those subjects who are unable to immunologically eliminate the virus so introduced.
This is particularly so when there is at present no cure for IBD; sufferers can expect relapses of their disease requiring potent immunosuppressant therapy or removal of the affected bowel and may be condemned to the use of a ostomomy bag. Nor is there a cure for autism; sufferers have to live in a silent world of their own unable to communicate with the rest of the world.
What is needed therefore is a safer vaccine which does not give rise to these problems, and a treatment for those with existing IBD. I have now discovered a combined vaccine/therapeutic agent which is not only most probably safer to administer to children and others by way of vaccination/immunisation, but which also can be used to treat IBD and RBD whether as a complete cure or to alleviate symptoms.
As disclosed in my earlier patent application Crohn""s Disease is most probably caused by a failure of the body to completely eliminate the measles virus, probably because of the failure of the initial dosage of virus to illicit a full immune response, which in turn allows the remaining virus to collect at various sites in the body particularly in the small intestine and colon thereby causing the granulomatous vasculitis associated with Crohn""s disease.
Although the mechanism of virus infection is not fully elucidated, it seems likely at present that the mechanism which gives rise to gut granuloma is as follows:
Following an incomplete immune response to an attenuated virus challenge in early life, or indeed less often a wild type infection, measles virus collects in the wall of the gut and particularly in the capillaries supplying blood thereto. At some point, often when a patient is between 20 to 30 years old, this induces a vasculitis which in turn causes necrosis of the overlying epithelium of the gut. I have previously shown that measles virus is present in these granulomatous lesions. It appears that for some reason lymphocytes which bind to the measles virus site fail to eliminate the virus so identified. What is needed therefore is a system for xe2x80x9cswitching onxe2x80x9d the destruct mechanisms of the bound lymphocytes which appear to be disenabled by the persistent measles virus particles.
The compositions of the present invention have the ability not only to condition the recipient to raise a specific immune response to MMR and measles virus when used as a vaccine/immunisation, but also to reestablish the appropriate antiviral immune response of an immune system to persistent measles virus infection in IBD.
I have also found that regressive behavioural disorder (RBD) in children is associated with measles, mumps and rubella (MMR) vaccination. Although it is yet to be established which element, if only one of MMR, for example measles virus, is directly implicated, histological and serological examination of a sample of children who exhibited RBD showed lesions in the gut indicative of the problems which arise in IBD and Crohn""s Disease. Further I have reviewed a cohort of children who following a period of apparent normality have lost acquired skills including those of communication. These children all have gastrointestinal symptoms including abdominal pain, diarrhoea, and in some cases food intolerance. It is significant that this syndrome only appeared with the introduction of the polyvalent MMR vaccine in 1988 rather than with the monovalent measles vaccine introduced in 1968. This indicates that MMR is responsible for this condition rather than just the measles virus and that accordingly a transfer factor (vide infra) specific for the components other than the measles virus in MMR maybe required.
In these children the mean interval from exposure to the MMR vaccine to the development of first behavioural symptom was six days, indicating a strong temporal association with exposure to the vaccine. Measles virus nucleocapsid protein antigen has been identified with the follicular dendritic cells in areas of lymphoid nodular hyperplasia in the affected intestine, further implicating a causal role for measles virus in this disease. These children exhibit immunodeficiencies associated with reduced numbers of circulating T lymphocytes. Specific boosting of antiviral immunity in these children could, therefore, be expected to be of therapeutic benefit.
Adoptive transfer of non-antigen-specific cell mediated immunity in humans was first demonstrated by Lawrence in Proc.Soc.Biol.Med 1949; 71; 516. This opened a new avenue of research that has led to an increased understanding of the basic immune mechanisms and to the development of many forms of immunomodulant therapy. Lawrence originally showed that transfer of intact, viable, lymphocytes from a normal tuberculin skin test-positive donor to a skin test-negative recipient, resulted in conversion (xe2x80x9ctransferxe2x80x9d) of the recipient to skin test-positivity.
Lawrence further demonstrated that delayed cutaneous hypersensitivity (DH) responsiveness could be transferred by a soluble, dialysed leucocyte extract (DLE). He termed the factor responsible for this phenomenon xe2x80x9ctransfer factorxe2x80x9d (TF). (TF) could transfer (DH) of a given specificity from a normal skin test-positive donor to a skin test-negative recipient. Moreover, within 6 months, leucocytes from the primary recipient could transfer specific (DH) to a previously skin test-negative secondary recipient.
In addition to transferring non-antigen-specific skin test positivity, DLE preparations containing TF can also initiate other non-antigen-specific cell mediated immune reactions including induction of cytokines such as macrophage migration inhibitory factor (MIF) and leucocyte migration inhibitory factor (LIF). The ability of TF to stimulate LIF production forms the basis for assessing, in vitro, the potency of non-antigen-specific TF.
Despite Lawrence""s work the considerable potential for TF as a therapeutic agent capable of transferring specific immunity to individuals who lacked such immunity was not recognised until about 1990. It has recently been used therefore in treatments for chickenpox, herpes virus infections, liver disease and in the treatment of HIV.
Generally human, mouse and bovine TF are small molecules of approximately 3500 to 6000 Daltons. TF is heat labile but cold stable; biological activity remains unimpaired after several years of storage at xe2x88x9220xc2x0 C. to xe2x88x9270xc2x0 C. Most studies of the effects of enzymes on the antigen-specific biological activity of TF indicate that it is composed of RNA bases attached to small peptides of at least 8 amino acids. If as seems likely each TF is antigen specific then individual TF""s may differ structurally in a manner similar to the subtle variations in antigen-binding sites at the hypervariable region of immunoglobulins or in the T cell receptor for antigens. This specificity is supported by the fact that TF specific for, for example, PPD antigen binds only PPD and no other antigen.
The mechanisms whereby TF participate in the cell-mediated immune response are simply not known. One hypothesis is that TF forms part of the T-lymphocyte receptor (TCR) for antigen and that its presence may be necessary for T cell activation. However, further supportive data are required that are compatible first with the activity of TF in the normal T cell mediated immune response and secondly with the ability of TF to transfer such immunity to a previously non-responsive recipient in an antigen-specific fashion.
In an antigen-responsive subject a small number of T cells bearing receptors for a given antigen are continually present. These membrane receptor sites probably include the TF moiety. Specific antigen binding to the appropriate receptor probably initiates production and the release of more TF which then binds to immunologically uncommitted T lymphocytes rendering them antigen-sensitive and responsive.
Similarly, in transfer of immunity to the non-responsive host, exogenous TF most probably binds to immunologically xe2x80x9cvirginxe2x80x9d cells. This binding may induce T cell receptor expression with the resulting complex of antigen-specific TF and the T cell receptor forming the specific antigen receptor on the T cell. However, induction of de novo synthesis of the T cell receptor or exposure of the relevant receptor to allosteric effects of transfer factor on membranes proteins should not be excluded.
Although little is known of the mechanism of the action of DLE-TF in vivo more is known of its effects in vitro. In vivo however DLE enhances graft rejection and augments lectin-dependant antibody dependent cellular cytotoxicity. This wide variety of effects of crude DLE reflects the activities of its many different moieties including non-specific adjuvant or inhibitory functions. Antigen-specific properties due to the TF moiety within the DLE include the ability to confer upon non-responsive lymphocytes the ability to react with the relevant antigen in vivo to produce lymphokines in vitro and to enhance antigen-specific T cells cytoxicity against tumour antigens by previously non-responsive cytotoxic cells.
DLE-TF is usually administered by subcutaneous or intramuscular injection, although oral administration appears equally effective. It can also be given intravenously or by suppository or by incorporation into liposomes to prolong its biological activity. Nothing is known about its pharmakinetics.
Further DLE-TF is remarkably free from adverse side effects. Given intramuscularly or subcutaneously an injection may cause pain at the injection site for 10 to 20 minutes and low-grade transient pyrexia may occur but no other significant problems have occurred. However severe pain can be induced at the site of primary or metastatic lesions caused by tumour necrosis when used in cancer therapy.
According therefore to the present invention there is provided a pharmaceutical composition for the treatment of an antigen specific MMR virus mediated disease comprising a soluble dialysed leucocyte extract comprising an antigen specific transfer factor (TF) disposed in a pharmaceutically acceptable carrier or diluent therefor, characterised in that the TF is antigen specific and is formed by the dialysis of virus-specific lymphocytes to a molecular cut-off of 12,500. The TF factor is particularly significant when directed to the measles virus alone but a TF factor for MMR, which is taken to include live attenuated measles vaccine virus, measles virus; mumps vaccine virus and rubella vaccine virus, and wild strains of the aforementioned viruses, or for the other components of MMR (mumps and rubella) is also useful especially for RBD.
The compositions may be particularly adapted for use as a vaccine/immunisation or for use as therapy for IBD or RBD. Preferably the transfer factor is a molecule of approximately 3,500 to 6000 Daltons which is cold stable. The compositions may be adapted for subcutaneous, intra muscular or intravenous injection or for administration by the oral route, by suppository or by incorporation into administrable liposomes.